The identity and topographic location of ocular inflammatory, degenerative, and tumor cells and their products in patient specimens and animal samples are analyzed by routine pathology, immunohistochemistry, and molecular pathology. The application of cutting-edge technology such as microdissection combined with PCR, RT-PCR, and RFLP techniques, allows us to provide more accurate pathological diagnosis (assessment) of the disease, and guiding us in selecting an appropriate therapy for the patient. We generate andor apply various animal models with ocular disorders, so we can learn the pathogenesis of different ocular diseases. This helps us to better understand disease pathogenesis and to select better therapies targeting specific diseases. In FY2007, we continued and accomplished the following in our research: [unreadable] [unreadable] 1. Detection of Genes and Proteins in Ocular Lymphoma Cells: We continue to confirm IgH gene rearrangements of ocular B-cell lymphoma using microdissection and PCR. In collaboration with Prof. LeHoang and her colleagues of France, we found elevation of aqueous interleukin (IL)-10 in 51 patients with primary intraocular lymphoma (PIOL) but not in the 108 uveitic patients, suggesting that IL-10 may be a good screening test to reduce delay in diagnosis. The defined diagnosis of PIOL requires the identification of PIOL cells in ocular tissues, which can be obtained from biopsies of the vitreous, retina andor subretinal tissues. We also reported a case of primary diffuse large B-cell lymphoma of the spleen with coincident serous retinal detachment responsive to corticosteroids. [unreadable] [unreadable] 2. Molecular Pathology of Age-Related Macular Degeneration (AMD): We detected higher rates of single nucleotide polymorphisms and higher expression of HtrA-1 in the AMD lesions compared to normal eyes, confirming the association studies of HtrA-1 gene and AMD. [unreadable] [unreadable] 3. New Pathology and Pathogenesis of Ocular Diseases: In collaboration with Dr. Liang of China, we described surgical resection of von Hippel-Lindau (VHL)-associated large retinal hemangioblastomas might be useful for therapy in select patients with VHL disease. We demonstrated CXCR4 expression for the first time in VHL-associated retinal tumor cells. We reported ocular resolution of autoimmune polyglandular syndrome associated keratopathy with keratolimbal stem cell transplantation. We also presented ophthalmic manifestations and histopathology of infantile nephropathic cystinosis. [unreadable] [unreadable] 4. Experimental Models for Various Ocular Diseases: We published a study showing that murine Ccl2Cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration (AMD). These mice present with clinical and pathological features of human AMD, such as drusen-like lesions, abnormal RPE cells and Bruchs membrane, and photorecptor degeneration as early as 4-5 weeks of age. Choroidal neovascularization also occurs in 15% of the animals. Elevation of A2E and decreased amounts of endoplasmic reticulum protein in the retina and RPE were also measured in the Ccl2Cx3cr1 deficient mice. The early onset and high penetrance of the disease make these mice an attarctive model for human AMD. [unreadable] [unreadable] In collaboration with Drs. Caspi, Gery, Hooks, and Nussenblatt of the NEI, several new modes and mechanisms of ocular inflammation have been discovered and published, which are described in their annual reports.